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Definitions

• the present invention relates to a novel adenine compound having an aromatic ring, useful as a therapeutic and/or preventive agent for allergic disease, viral disease or cancer, etc.
• immune systems exist in order to exclude said substances.
• antigen processing by antigen presenting cells such as dendritic cells (DCs) is carried out when the foreign substances invade, and naive Th cells functionally differentiate via interactions of DCs/Th cells into Th1 or Th2 cells which play a central role of immune response in a body. It is reported that immune diseases are developed by one-way deflection of immuno-balance of Th1 or Th2 cells in this process.
• an excess amount of cytokine such as interleukin-4 (IL-4) and interleukin-5 (IL-5) secreted by Th2 cells is secreted in patients with allergic diseases, and the compound inhibiting immune response of Th2 cells may be expected to be a therapeutic agent for allergic disease. Also, the compound enhancing immune response of Th1 cells may be expected to be a therapeutic or preventive agent for viral disease or cancer.
• IL-4 interleukin-4
• IL-5 interleukin-5
• TLR Toll-like receptor
• a ligand of TLR may be expected to have a function as a Th1/Th2 differentiation controlling agent and to be useful for treatment or prevention of immune diseases in that TLR recognizes a ligand to induce inflammatory cytokine such as IL-12, TNF, and IL-12 differentiates and induces naive T cell to Th1 cell.
• Th2 cell predominates in patients with asthma, atopic dermatitis, etc., and asthma-targeted clinical trials are carried out for DNA (CpGDNA) derived from microorganism, TLR9 agonist.
• TLR7/8 agonist, imidazoquinoline derivative also shows an inhibitory activity toward the production of Th2 cytokine interleukin-4 (IL-4) and interleukin-5 (IL-5), and is actually useful for allergic diseases in experimental animal models.
• compounds described in, for example, Patent Documents 2 to 4 are known as compounds with adenine structures which are effective for immune diseases such as viral diseases and allergic diseases.
• TLR activator more particularly a novel adenine compound which activates as a TLR7 activator, and an immune-response modifier comprising the same as an active ingredient, for example, a therapeutic or preventive agent for allergic disease such as asthma, COPD, allergic rhinitis, allergic conjunctivitis or atopic dermatitis, viral disease such as hepatitis B, hepatitis C, HIV or HPV, bacterial infectious disease, cancer or dermatitis, etc.
• a therapeutic or preventive agent for allergic disease such as asthma, COPD, allergic rhinitis, allergic conjunctivitis or atopic dermatitis
• viral disease such as hepatitis B, hepatitis C, HIV or HPV, bacterial infectious disease, cancer or dermatitis, etc.
• the present inventors found the novel adenine compounds of the present invention according to their intensive study in order to obtain a therapeutic or preventive agent for immune diseases such as allergic disease, viral disease or cancer with excellent TLR activating action.
• the compounds of the present invention are effective as a therapeutic or preventive agent for allergic disease, viral disease, or cancer, etc.
• the present invention has been achieved on the basis of the above knowledge. Specifically, the present invention relates to the following inventions.
• the present invention enables to provide useful and novel adenine compounds as a therapeutic or preventive agent for allergic disease, viral disease or cancer, etc.
• halogen as used herein includes fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
• alkyl includes straight chain or branched chain alkyl with 1 to 12 carbon atom(s), particularly, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1-methylpropyl, 1, 1-dimethylethyl, pentyl, 3-methylbutyl, 2-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1, 1-dimethylpropyl, hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1, 1-dimethylbutyl, 1 2-dimethylbutyl, heptyl, 1-methylhexyl, 1-ethyl
• alkenyl includes straight chain or branched chain alkenyl with 2 to 10 carbon atoms, particularly, ethenyl, propenyl, 1-methylethenyl, butenyl, 2-methylpropenyl, 1-methylpropenyl, pentenyl, 3-methylbutenyl, 2-methylbutenyl, 1-ethylpropenyl, hexenyl, 4-methylpentenyl, 3-methylpentenyl, 2-methylpentenyl, 1-methylpentenyl, 3,3-dimethylbutenyl, 1 2-dimethylbutenyl, heptenyl, 1-methylhexenyl, 1-ethylpentenyl, octenyl, 1-methylheptenyl, 2-ethylhexenyl, nonenyl, decenyl, etc.
• alkenyl with 2 to 6 carbon atoms Preferable one is alkenyl with 2 to 6 carbon atoms, more preferably, alkenyl with 2 to 4 carbon atoms.
• alkynyl includes straight chain or branched chain alkynyl with 1 to 10 carbon atoms, particularly, ethynyl, propynyl, butynyl, pentynyl, 3-methylbutynyl, hexynyl, 4-methylpentynyl, 3-methylpentynyl, 3,3-dimethylbutynyl, heptynyl, octynyl, 3-methylheptynyl, 3-ethylhexynyl, nonyl, or decynyl, etc.
• alkynyl with 2 to 6 carbon atoms Preferable one is alkynyl with 2 to 6 carbon atoms, more preferably, alkynyl with 2 to 4 carbon atoms
• cycloalkyl includes 3- to 8-membered monocyclic cycloalkyl, particularly, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Preferable one is 4- to 6-membered cycloalkyl.
• cycloalkoxy includes 3- to 8-membered monocyclic cycloalkoxy, particularly, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy or cyclooctyloxy.
• aryl includes 6- to 10-membered aryl, particularly, phenyl, 1-naphthyl or 2-naphthyl. Preferable one is phenyl.
• heteroaryl includes 5- to 10-membered mono- or bi-cyclic heteroaryl containing 1 to 4 heteroatom(s) selected from 0 to 2 nitrogen(s), 0 to 1 oxygen and 0 to 1 sulfur, particularly, furyl, thienyl, pyrrolyl, pyridyl, indolyl, isoindolyl, quinolyl, isoquinolyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, etc.
• Substituents may bind on any carbon or nitrogen atom where it may be kept in chemically stable state without any limitation for binding positions.
• Preferable one is 5- or 6-membered heteroaryl.
• saturated heterocycle includes 4- to 10-membered mono- or bi-cyclic saturated heterocycle containing 1 to 4 heteroatom(s) selected from 0 to 3 nitrogen(s), 0 to 1 oxygen and 0 to 1 sulfur, particularly, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, perhydroazepinyl, perhydrodiazepinyl (homopiperazinyl), morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1, 1-dioxothiomorpholinyl, tetrahydrofuranyl, etc.
• Substituents may bind on any carbon or nitrogen atom where it may be kept in chemically stable state without any limitation for binding positions.
• Preferable one is 4- to 8-membered monocyclic saturated heterocycle, more preferably, 4- to 6-membered saturated heterocycle.
• alkylene includes straight chain or branched chain alkylene with 1 to 12 carbon atom(s), particularly, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene, 2-methylethylene, 1-methyltrimethylene, 2-methyltrimethylene, 2-methyltetramethylene, or 3-methylpentamethylene, etc.
• Preferable one is straight chain or branched chain alkylene with 1 to 10 carbon atom(s), more preferably, with 1 to 8 carbon atom(s), more preferably, with 1 to 6 carbon atom(s).
• the substituents of the substituted alkylene include hydroxy, amino, alkylamino, dialkylamino.
• haloalkyl includes alkyl substituted with 1 to 5 of the same or different halogen(s), particularly, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, 2-fluoroethyl, 4,4,4-trifluorobutoxy, pentafluoroethyl, etc.
• alkoxy includes straight chain or branched chain alkoxy with 1 to 10 carbon atom(s), particularly, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, 1-methylpropoxy, 1, 1-dimethylethoxy, pentoxy, 3-methylbutoxy, 2-methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, 1, 1-dimethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1, 1-dimethylbutoxy, 1 2-dimethylbutoxy, heptyloxy, 1-methylhexyloxy, 1-ethylpentyloxy, octyloxy, 1-methylheptyloxy, 2-ethylhexyloxy, nonyloxy, decyloxy, etc.
• haloalkoxy includes alkoxy substituted with 1 to 5 of the same or different halogen(s), particularly, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2-fluoroethoxy, 4, 4, 4-trifluorobutoxy, pentafluoroethoxy, etc.
• alkyl in “alkylthio”, “alkylcarbonyl”, “alkylcarbonyloxy”, “alkylsulfonyl", “alkylsulfinyl”, “alkylamino”, “dialkylamino”, “alkylcarbamoyl”, “dialkylcarbamoyl”, “alkylsulfamoyl” and “dialkylsulfamoyl” includes the same as the alkyl group as defined above.
• alkylthio includes straight chain or branched chain alkylthio with 1 to 10 carbon atom(s), particularly, alkylthio with 1 to 6 carbon atom(s), more preferably, alkylthio with 1 to 4 carbon atom(s).
• alkylcarbonyl particularly includes straight chain or branched chain alkylcarbonyl with 2 to 11 carbon atom(s), preferably, with 2 to 6 carbon atom(s), more preferably, with 2 to 5 carbon atom(s).
• alkylcarbonyloxy includes straight chain or branched chain alkylcarbonyloxy with 2 to 11 carbon atoms, more preferably, with 2 to 6 carbon atoms, more preferably, with 2 to 5 carbon atoms.
• alkylsulfonyl includes straight chain or branched chain alkylsulfonyl with 1 to 10 carbon atom(s), more preferably, with 1 to 6 carbon atom(s), more preferably, with 1 to 4 carbon atom(s).
• alkylsulfinyl includes straight chain or branched chain alkylsulfinyl with 1 to 10 carbon atom(s), more preferably, with 1 to 6 carbon atom(s), more preferably, with 1 to 4 carbon atom(s).
• alkylamino includes amino substituted with an alkyl group having 1 to 10 carbon atom(s), preferably, 1 to 6 carbon atom(s), more preferably, 1 to 4 carbon atom(s).
• dialkylamino includes amino substituted with the same or different two alkyl group(s) having 1 to 10 carbon atom(s), preferably, 1 to 6 carbon atom(s), more preferably, 1 to 4 carbon atom(s).
• alkylcarbamoyl includes carbamoyl substituted with an alkyl group having 1 to 10 carbon atom(s), preferably, 1 to 6 carbon atom(s), more preferably, 1 to 4 carbon atom(s).
• dialkylcarbamoyl includes carbamoyl substituted with the same or different two alkyl group(s) having 1 to 10 carbon atom(s), preferably, 1 to 6 carbon atom(s), more preferably, 1 to 4 carbon atom(s).
• alkylsulfamoyl includes sulfamoyl substituted with an alkyl group having 1 to 10 carbon atom(s), preferably, 1 to 6 carbon atom(s), more preferably, 1 to 4 carbon atom(s).
• dialkylsulfamoyl includes sulfamoyl substituted with the same or different two alkyl group(s) having 1 to 10 carbon atom(s), preferably, 1 to 6 carbon atom(s), more preferably, 1 to 4 carbon atom(s).
• alkoxy in “alkoxycarbonyl” includes the same as the alkoxy group as defined above. Specifically, “alkoxycarbonyl” includes straight chain or branched chain alkoxycarbonyl with 2 to 11 carbon atoms, preferably, with 2 to 6 carbon atoms, more preferably, with 2 to 5 carbon atoms.
• cycloalkyl in “cycloalkylcarbonyl”, “cycloalkylsulfonyl” and “cycloalkylsulfinyl” includes the same as the cycloalkyl group as defined above.
• cycloalkylcarbonyl particularly includes 3- to 8-membered monocyclic cycloalkylcarbonyl, preferably, 4- to 6-membered monocyclic cycloalkylcarbonyl.
• cycloalkylsulfonyl particularly includes 3- to 8-membered monocyclic cycloalkylsulfonyl, preferably, 4- to 6-membered monocyclic cycloalkylsulfonyl.
• cycloalkylsulfinyl particularly includes 3- to 8-membered monocyclic cycloalkylsulfinyl, preferably, 4- to 6-membered monocyclic cycloalkylsulfinyl.
• cycloalkoxy in “cycloalkoxycarbonyl” includes the same as the cycloalkoxy group as defined above.
• cycloalkoxycarbonyl includes 3- to 8-membered monocyclic cycloalkoxycarbonyl, preferably, 4- to 6-membered cycloalkoxycarbonyl.
• aryl in “aryloxy”, “arylcarbonyl”, “aryloxycarbonyl”, “arylsulfonyl”, “arylsulfinyl”, “arylalkyl” and “aryloxyalkyl” includes the same as the aryl group as defined above.
• aryloxy includes phenoxy, 1-naphthoxy or 2-naphthoxy.
• arylcarbonyl includes benzoyl, 1-naphthaloyl or 2-naphthaloyl.
• aryloxycarbonyl includes phenoxycarbonyl, 1-naphthoxycarbonyl or 2-naphthoxycarbonyl.
• arylsulfonyl includes phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl.
• arylsulfinyl includes phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl.
• arylalkyl includes straight chain or branched chain alkyl with 1 to 10 carbon atoms, particularly, with 1 to 6 carbon atoms, more particularly, with 1 to 4 carbon atoms, which is substituted with aryl.
• the "aryl” includes phenyl.
• the “aryloxyalkyl” includes straight chain or branched chain alkyl with 1 to 10 carbon atoms, particularly, with 1 to 6 carbon atoms, more particularly, with 1 to 4 carbon atoms, which is substituted with the "aryloxy” as defined above.
• the “aryloxy” includes phenoxy.
• the term “heteroaryl” in “heteroaryloxy”, “heteroarylcarbonyl”, “heteroaryloxycarbonyl”, “heteroarylsulfonyl”, “heteroarylsulfinyl", “heteroarylalkyl", and “heteroaryloxyalkyl” includes the same as the heteroaryl as defined above.
• heteroaryloxy includes pyrrolyloxy, pyridyloxy, pyrazinyloxy, pyrimidinyloxy, pyridazinyloxy, furyloxy, thienyloxy.
• heteroarylcarbonyl includes pyrrolylcarbonyl, pyridylcarbonyl, pyrazinylcarbonyl, pyrimidinylcarbonyl, pyridazinylcarbonyl, furylcarbonyl, thienylcarbonyl, etc.
• heteroaryloxycarbonyl includes pyrrolyloxycarbonyl, pyridyloxycarbonyl, pyrazinyloxycarbonyl, pyrimidinyloxycarbonyl, pyridazinyloxycarbonyl, furyloxycarbonyl, thienyloxycarbonyl.
• heteroarylsulfonyl includes pyrrolylsulphonyl, pyridylsulphonyl, pyrazinylsulphonyl, pyrimidinylsulphonyl, pyridazinylsulphonyl, furylsulphonyl, thienylsulphonyl.
• heteroarylsulfinyl includes pyrrolylsulfinyl, pyridylsulfinyl, pyrazinylsulfinyl, pyrimidinylsulfinyl, pyridazinylsulfinyl, furylsulfinyl, thienylsulfinyl.
• the “heteroarylalkyl” includes straight chain or branched chain alkyl with 1 to 10 carbon atoms, particularly, with 1 to 6 carbon atoms, more particularly, with 1 to 4 carbon atoms, which is substituted with the heteroaryl group as defined above.
• heteroaryloxyalkyl includes straight chain or branched chain alkyl with 1 to 10 carbon atoms, particularly, with 1 to 6 carbon atoms, more particularly, with 1 to 4 carbon atoms, which is substituted with the heteroaryloxy group as defined above.
• the "heteroaryl” includes pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl.
• nitrogen-containing saturated heterocycle used herein includes, preferably, 4- to 8-membered nitrogen-containing saturated heterocycle containing 1 to 4 heteroatom(s) selected from 1 to 3 nitrogen(s), 0 to 1 oxygen and 0 to 1 sulfur.
• the "nitrogen-containing saturated heterocycle” formed by combining R 2 with L 2 may include pyrrolidine, piperidine, piperazine, morpholine or the like.
• the "NR 2 R 3 ", wherein R 2 is combined together with R 3 to form a nitrogen-containing saturated heterocycle, includes preferably the nitrogen-containing saturated heterocycle of the formulae (2) to (8):
• R 10 is the substituent of the nitrogen-containing saturated heterocycle as defined above, which may bind to any carbon atoms and imino.
• R 10 may include halogen; hydroxy; oxo; alkyl with 1 to 6 carbon atom(s), alkoxy with 1 to 6 carbon atom(s), alkylcarbonyl with 2 to 6 carbon atoms, wherein said alkyl, alkoxy and alkylcarbonyl is optionally substituted with 1 to 3 substituent(s) selected from halogen, cyano, hydroxy, alkoxy with 1 to 6 carbon atom(s), substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy, amino optionally substituted with the same or different one or two alkyl(s) with 1 to 6 carbon atom(s), and carbamoyl optionally substituted with the same or different one or two alkyl(s) with 1 to 6 carbon atom(s); 3- to 6-membered cycloalkyl
• Said substituted phenyl, substituted phenoxy, substituted heteroaryl and substituted heteroaryloxy may be those substituted with one or more group(s) selected from halogen, hydroxy, alkyl with 1 to 6 carbon atom(s), alkoxy with 1 to 6 carbon atom(s), amino optionally substituted with the same or different one or two alkyl(s).
• "NR 2 R 3 " includes preferably the groups of the formulae (3) and (7) as represented above, when the group L 2 is a single bond.
• the aromatic carbocycle in A includes benzene ring or naphthalene ring without any limitation for binding position. Since said ring A is divalent in the formula (1), any two hydrogens on the ring should involve in the linkages.
• the aromatic heterocycle in A includes 5- to 10-membered mono- or bi-cyclic aromatic heterocycle containing 1 to 4 heteroatom(s) selected from 0 to 3 nitrogen(s), 0 to 1 oxygen and 0 to 1 sulfur without any limitation for binding position, where it may be kept in chemically stable state.
• the aromatic heterocycle particularly includes furan, thiophen, pyrrole, pyridine, indole, isoindole, quinoline, isoquinoline, pyrazole, imidazole, pyrimidine, pyrazine, pyridazine, thiazole or oxazole, etc.
• 5- to 6- membered monocyclic aromatic heterocycle is preferable. Since ring A is divalent in the formula (1), any two hydrogens on the ring should involve in the linkages.
• aromatic carbocycle and aromatic heterocycle in A may be substituted with the same or different 1 to 3 substituent(s), wherein the substituent includes halogen, hydroxy, nitro, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylsulfonyl alkylsulfinyl, and amino optionally substituted with one or two alkyl(s).
• Said methylene group may be replaced preferably with oxygen, sulfur, SO, SO 2 or carbonyl, more preferably with oxygen.
• the compounds of the formula (1) may be that wherein L 1 and L 2 are both methylene, or L 1 is methylene and L 2 is the group of the formula: -O- (CH 2 ) n wherein n is an integer of 2 to 4.
• the compounds of the formula (1) may be that wherein A is pyridine; L 1 is methylene; L 2 is the group of the formula: -O- (CH 2 ) n wherein n is an integer of 2 to 4, NR 2 R 3 is amino, alkylamino, dialkylamino, or the group of any one of the formulae (2) to (8) as represented above.
• the compounds of the formula (1) may be that wherein A is pyridine; L 1 is methylene; L 2 is a single bond, NR 2 R 3 is the group of the formula (3) as represented above.
• 4- to 8-membered saturated heterocycle to which two substituents of substituted amino are combined together with the mitrogen atom, includes 4- to 8-membered saturated heterocycle with 1 to 4 heteroatom(s) selected from 1 to 3 nitrogen(s), 0 to 1 oxygen and 0 to 1 sulfur, and it may bind on any positions without any limitation where it may be kept in chemically stable state.
• the sulfur atom may be substituted with 1 or 2 oxygen atom(s).
• Suitable examples are azetidine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholin-1-oxide, thiomorpholine-1,1-dioxide, 1,4-perhydrodiazepine, perhydroazepine, imidazolidine, oxazolidine, etc.
• X is preferably oxygen or a single bond.
• R 7 is preferably hydrogen or alkyl with 1 to 3 carbon atom(s), more preferably, hydrogen or methyl.
• R 1 is preferably substituted or unsubstituted straight chain or branched chain alkyl with 1 to 6 carbon atom(s), more preferably, substituted or unsubstituted straight chain alkyl with 1 to 4 carbon atom(s), and particularly comprises substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl, 1-methylethyl, 1-methylpropyl, 2-methylbutyl, etc.
• R 1 is substituted alkyl
• the substituent of the alkyl preferably includes halogen, hydroxy, straight chain or branched chain alkoxy with 1 to 4 carbon atom(s), straight chain or branched chain alkylthio with 1 to 4 carbon atom(s), 3- to 6-membered cycloalkyl, phenyl, 5- to 6-membered heteroaryl, wherein said cycloalkyl, phenyl and heteroaryl are optionally substituted with halogen, hydroxy, alkyl with 1 to 6 carbon atom(s) or alkoxy with 1 to 6 carbon atom(s).
• the substituent includes fluorine, hydroxy, cyclopropyl or straight chain or branched chain alkoxy with 1 to 3 carbon atom(s), which may be substituted with the same or different one or more, preferably one to five, more preferably one to three, substituent(s).
• the R 1 particularly includes methyl, ethyl, propyl, butyl, pentyl, 1-methylethyl, 1-methylpropyl, 2-methylbutyl, 2-methoxyethyl, cyclopropylmethyl, 2,2,2-trifluoroethyl, 4, 4, 4-trifluorobutyl, 4-pyridylmethyl, etc.
• the adenine compounds of the present invention are intended to include all tautomers, geometric isomers or stereoisomers, and optionally, a mixture thereof depending on the kinds of substituents.
• diastereomers and enantiomers may also exist, and the present invention includes the diastereomers, the enantiomers, and mixtures and isolated forms thereof.
• the adenine compound of the formula (1) and a tautomer thereof are chemically equivalent, and the adenine compound of the present invention also includes the tautomer thereof.
• the tautomer is in the form of hydroxy of the formula (1'):
• a pharmaceutically acceptable salt includes acid addition salt and base addition salt.
• the acid addition salt includes an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, phosphate, etc., and an organic acid salt such as citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, fumarate, maleate, succinate, tartrate, lactate, pyruvate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, etc.
• the base addition salt includes an inorganic base salt such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, etc., and an organic base salt such as triethyl ammonium salt, triethanol ammonium salt, pyridinium salt, diisoprop
• the compound of the general formula (1) may be prepared by the following methods. Starting compounds which are not described below may be prepared according to the following methods or known methods or those similar thereto.
• L, L' and L" are leaving groups which may be the same or different each other; A, R 1 , R 2 , R 3 , X, L 1 and L 2 are as defined above.
• a protection or deprotection technique may be applied, if necessary.
• a preferable protective group, a method for protection and deprotection are particularly described in " Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.; 1990 )", etc.
• Compound (I-I) may be reacted with compound (I-VIII) in the presence of a base to give compound (I-II).
• the base which may be used therein includes alkali metal carbonate such as sodium carbonate or potassium carbonate, alkaline earth metal carbonate such as calcium carbonate, metal hydroxide such as sodium hydroxide or potassium hydroxide, metal hydride such as sodium hydride, or metal alkoxide such as potassium t-butoxide, etc.
• the solvent which may be used therein includes aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile, halogenated hydrocarbon solvent such as carbon tetrachloride, chloroform or methylene chloride, ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, etc.
• the reaction temperature is selected from the range of about 0°C to around a boiling point of the solvent.
• the compound of formula (1) may be obtained by treating the compound (I-II) under an acidic condition.
• the acid used in the acid-treatment includes an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid, etc.
• the solvent which may be used therein includes water, or a mixture of water and an organic solvent.
• the organic solvent includes ether solvent such as diethyl ether or tetrahydrofuran, aprotic solvent such as N,N-dimethylformamide or acetonitrile, or alcoholic solvent such as methanol or ethanol, etc.
• the reaction temperature is, for example, selected from the range of room temperature to around a boiling point of the solvent.
• the conversion of methoxy on 8-position of the adenine ring into oxo by acid treatment may be carried out not in the final step but in any steps.
• Compound (I-VIII) may be prepared by the following methods.
• L, L', A, R 2 , R 3 , L 1 and L 2 are as defined above.
• Compound (I-IX) may be reacted with compound (I-X) in the similar manner to the above to give compound (I-VIII).
• compound (I-IX) may be reacted with compound (I-XI) in the similar manner to the above to give compound (I-XIX), followed by reacting with compound (I-XII) in the similar manner to the above to give compound (I-VIII).
• Compound (I-IX) may be known in the art or prepared from any known compound in a manner known to those skilled in the art.
• compound (I-I) may be also reacted with compound (I-IX) in the similar manner to the above to give compound (I-IV), followed by reacting with compound (I-X) in the similar manner to the above to give compound (I-II).
• compound (I-I) may be also reacted with compound (I-XIV) in the similar manner to the above to give compound (I-VI), followed by reacting with compound (I-XV) in the similar manner to the above to give compound (I-IV).
• compound (I-I) may be also reacted with compound (I-XVI) in the similar manner to the above to give compound (I-VII), followed by reacting with compound (I-XXVI) in the similar manner to the above to give compound (I-II).
• Compound (I-I) may be prepared according to the following methods.
• R 1 and X are as defined above.
• Compound (I-XVIII) may be reacted with ammonia in aqueous solution, organic solvent or a mixture of water and organic solvent to give compound (I-XIX).
• the organic solvent includes alcoholic solvent such as methanol, ethanol, propanol or butanol, ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, aprotic solvent such as acetonitrile, etc.
• the reaction temperature is selected from the range of room temperature to 200°C.
• a reaction container such as autoclave may be used in the reaction.
• Compound (I-XIX) may be brominated to give compound (I-XX).
• a brominating agent which may be used therein includes bromine, hydrobromic acid perbromide or N-bromosuccinimide, etc., and for example, a reaction auxiliary such as sodium acetate may be added to the reaction.
• the solvent which may be used therein includes halogenated hydrocarbon solvent such as carbon tetrachloride, methylene chloride or dichloroethane, ether solvent such as diethyl ether, acetic acid, or carbon disulfide, etc.
• the reaction temperature is selected from the range of about 0°C to around a boiling point of the solvent.
• Compound (I-XX) may be reacted with sodium methoxide to give compound (I-XXI).
• the organic solvent which may be used therein includes ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, aprotic solvent such as N,N-dimethylformamide, or alcoholic solvent such as methanol, etc.
• the reaction temperature is selected from the range of room temperature to around a boiling point of the solvent.
• Compound (I-XX) may be also treated in an aqueous alkaline solution containing methanol to give compound (I-XXI).
• the aqueous alkaline solution which may be used therein includes an aqueous solution of alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.
• the reaction temperature is selected from the range of room temperature to around a boiling point of the solvent.
• Compound (I-XXI) may be reacted with compound (I-XXV) to give compound (I-XXII).
• the reaction is carried out in the presence or absence of a base in case that X is NR 7 wherein R 7 is hydrogen or alkyl.
• the base which may be used therein includes alkali metal carbonate such as sodium carbonate or potassium carbonate, alkaline earth metal carbonate such as calcium carbonate, metal hydroxide such as sodium hydroxide or potassium hydroxide, or an organic base such as triethylamine, diisopropylethylamine or 4-dimethylaminopyridine, etc.
• the solvent which may be used therein includes ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, alcoholic solvent such as propanol or butanol, or aprotic solvent such as N,N-dimethylformamide, or the reaction may be carried out in the absence of solvent.
• the reaction temperature is selected from the range of about 50°C to 200°C.
• the reaction is carried out in the presence of a base in case that X is oxygen or sulfur.
• the base which may be used therein includes alkali metal such as sodium or potassium, or alkali metal hydride such as sodium hydride.
• the solvent which may be used therein includes ether solvent such as tetrahydrofuran, 1,4-dioxane or diglyme, or aprotic solvent such as N,N-dimethylformamide or dimethylsulfoxide, or the reaction may be carried out in the absence of solvent.
• the reaction temperature is selected from the range of about 50°C to 200°C.
• reaction may be carried out by oxidizing the corresponding intermediate for preparation wherein X is sulfur with oxoneTM or m-chloroperbenzoic acid (mCPBA) in case that X is SO 2
• compound (I-XIX) in the preparation step from compound (I-XIX) to compound (I-XXII), compound (I-XXIII) may be synthesized in the similar manner to the above to give compound (I-XXIV), followed by obtaining compound (I-XXII).
• Compound (I-XXII) may be treated with an acid in an organic solvent such as methanol to give compound (I-I).
• the acid which may be used therein includes an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid, or an organic acid such as trifluoroacetic acid.
• the solvent which may be used therein includes water, or a mixture of water and an organic solvent.
• the organic solvent includes ether solvent such as diethyl ether or tetrahydrofuran, aprotic solvent such as N,N-dimethylformamide or acetonitrile, or alcoholic solvent such as methanol or ethanol.
• the reaction temperature is selected from the range of room temperature to around a boiling point of the solvent.
• Compound (I-I) may be prepared according to the following methods in case that X is NR 7 CO wherein R 7 is as defined above.
• R 1 and R 7 is as defined above.
• Compound (I-XIX) is reacted with methanethiol in the presence of a base to give Compound (I-XXVII).
• Suitable base includes, for example, alkali metals such as sodium and potassium, or alkali metal hydrides such as sodium hydride.
• Compound (I-XXVIII) may be prepared by oxidating compound (I-XXVII) with oxone or m-chloroperhydrobenzoate (mCPBA).
• Compound (I-XXVIII) may be treated with sodium cyanide or potassium cyanide to give compound (I-XXIX).
• Compound (I-XXIX) may be hydrolyzed with alkaline aqueous solution to give Compound (I-XXX).
• Compound (I-XXX) may be brominated at 8-posion of the adenine in a similar manner to the above to give compound (I-XXXI), which is methoxylated to afford compound (I-XXXII).
• Compound (I-XXXII) may be converted to an amide compound (I-XXXIV), which has been substituted with various substituents.
• compound (I-XXXII) can be condensed with amine (compound (I-XXXIII)) in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) can afford the corresponding amido compound (compound I-XXXIV).
• a condensing agent such as dicyclohexylcarbodiimide (DCC)
• DCC dicyclohexylcarbodiimide
• Compound (I-XXXIV) may be treated with trifluoroacetate in an organic solvent such as methanol to geve Compound (I-I).
• the compound of the general formula (1) may be also prepared by the following methods using compound (II-I) as a starting compound.
• the starting compound (II-I) is disclosed in WO 2002/085905 and WO 2004/029054 in detail. Starting compounds which are not described below may be prepared according to the following methods or known methods or those similar thereto.
• compound (II-I) may be reacted with compound (I-VIII) in the presence of a base to give compound (II-II).
• the base which may be used therein includes alkali metal carbonate such as sodium carbonate or potassium carbonate, alkaline earth metal carbonate such as calcium carbonate, metal hydroxide such as sodium hydroxide or potassium hydroxide, metal hydride such as sodium hydride, or metal alkoxide such as potassium t-butoxide.
• the solvent which may be used therein includes aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile, halogenated hydrocarbon solvent such as carbon tetrachloride, chloroform or methylene chloride, ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane.
• aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide or acetonitrile
• halogenated hydrocarbon solvent such as carbon tetrachloride, chloroform or methylene chloride
• ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane.
• the reaction temperature is selected from the range of about 0°C to around a boiling point of the solvent.
• Compound (1) may be obtained in a similar manner to Preparation Method 1 from compound (II-II).
• compound (II-II) may be obtained via synthesis of compound (II-IV), compound (II-V) or compound (II-VI), in a similar manner to Preparation Method 1.
• L, L', L", A, R 1 , R 2 , R 3 , X, L 1 and L 2 are as defined above.
• Compound (II-II) may be brominated to give compound (II-III).
• a brominating agent which may be used therein includes bromine, hydrobromic acid perbromide or N-bromosuccinimide, etc., and for example, a reaction auxiliary such as sodium acetate may be added to the reaction.
• the solvent which may be used therein includes halogenated hydrocarbon solvent such as carbon tetrachloride, methylene chloride or dichloroethane, ether solvent such as diethyl ether, acetic acid, or carbon disulfide, etc.
• the reaction temperature is selected from the range of about 0°C to around a boiling point of the solvent.
• Compound (II-III) may be reacted with metal alkoxide such as sodium methoxide to give compound (I-II).
• the solvent which may be used in the reaction with metal alkoxide includes ether solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, aprotic solvent such as N,N-dimethylformamide, or alcoholic solvent corresponding to metal alkoxide used therein such as methanol, etc.
• the reaction temperature is selected from the range of room temperature to around a boiling point of the solvent.
• compound (I-II) may be obtained using compound compound (II-I), compound (II-II), compound (II-IV), compound (II-V) and compound (II-VI), via bromination at 8-position and the steps in the similar manner to the above sinthesis from compound (II-I) to compound (II-II).
• adenine compounds, intermediates or starting compounds thereof with any functional groups in the present invention may be optionally subjected to homologation reaction, substituent introduction reaction or functional group transformation reaction, etc. in an appropriate step, or more specifically, in any halfway step of each preparation method described in the above Preparation Method 1 or 2 according to a conventional method known to those skilled in the art.
• a method described in " Jikken-Kagaku-Koza (edited by the Chemical Society of Japan, Maruzen )", or " Comprehensive Organic Transformation, Author: R. C. Larock, (VCH Publishers, Inc, 1989 )", etc. may be used.
• the homologation reaction includes, for example, a method wherein ester is converted into hydroxymethyl using a reducing agent such as lithium aluminum hydride, followed by introducing a leaving group to introduce cyano, etc.
• the functional group transformation reaction includes, for exmaple, acylation or sulfonylation reaction using acid halide, sulfonyl halide, etc., a reaction using alkylating agent such as halogenated alkyl, carbon-carbon bond formation reaction such as hydrolysis reaction, Friedel-Crafts reaction or Wittig reaction, oxidation or reduction reaction, etc.
• a protection or deprotection technique may optionally be applied.
• a preferable protective group, a method for protection and deprotection are specifically described in " Protective Groups in Organic Synthesis 2nd Edition (John Wiley & Sons, Inc.; 1990 )", etc.
• the compound of the formula (1) or an intermediate for preparing the same of the present invention may be purified by a method known to those skilled in the art. For example, it may be purified by column chromatography (e.g., silica gel column chromatography, or ionexchange column chromatography), or recrystallization, etc.
• the solvent which may be used in the recrystallization includes, for example, alcoholic solvents such as methanol, ethanol or 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as benzene or toluene, ketone solvents such as acetone, hydrocarbon solvents such as hexane, aprotic solvents such as N,N-dimethylformamide or acetonitrile, water, or a mixture thereof, etc.
• Other purification methods include a method described in Jikken-Kagaku-Koza (edited by the Chemical Society of Japan, Maruzen), vol. 1 , etc.
• the compound of the formula (1) with one or more asymmetric center(s) of the present invention may be prepared by using a starting material with asymmetric centers or introducing asymmetric centers in any half way steps according to a conventional method.
• enantiomers may be obtained by using optically active starting materials or carrying out optical resolution in an appropriate step of the preparation method.
• the optical resolution may be carried out by a diastereomeric method wherein the compound of the formula (1) or an intermediate thereof is reacted with an optically active acid (e.g., monocarboxylic acid such as mandelic acid, N-benzyloxyalanine or lactic acid, dicarboxylic acid such as tartaric acid, o-diisopropylidene tartaric acid or malic acid, or sulfonic acid such as camphorsulfonic acid or bromocamphorsulfonic acid) to form a salt thereof in an inactive solvent (e.g., alcoholic solvent such as methanol, ethanol or 2-propanol, ether solvent such as diethyl ether, ester solvent such as ethyl acetate, hydrocarbon solvent such as toluene, or aprotic solvent such as acetonitrile, and a mixture thereof).
• an optically active acid e.g., monocarboxylic acid such as mandelic acid, N-
• the optical resolution may be also carried out by reacting the compound of the formula (1) or an intermediate thereof having an acidic functional group such as carboxy with an optically active amine (e.g., organic amine such as ⁇ -phenethylamine, kinin, quinidine, cinchonidine, cinchonine, strychnine) to form a salt thereof.
• an optically active amine e.g., organic amine such as ⁇ -phenethylamine, kinin, quinidine, cinchonidine, cinchonine, strychnine
• a temperature for forming the salt is selected from the range of room temperature to a boiling point of the solvent. In order to improve an optical purity, it is desirable to raise the temperature up to around a boiling point of the solvent.
• the precipitated salt may be cooled in filtration to improve its yield as necessary.
• the usage of an optically active acid or amine is properly in the range of about 0.5 to about 2.0 equivalents, preferably around 1 equivalent, to the substrate.
• the crystal may be also, as necessary, recrystallized in an inactive solvent (e.g., alcoholic solvent such as methanol, ethanol, 2-propanol, ether solvent such as diethyl ether, ester solvent such as ethyl acetate, hydrocarbon solvent such as toluene, aprotic solvent such as acetonitrile, and a mixture thereof) to give an optically active salt in high purity.
• an inactive solvent e.g., alcoholic solvent such as methanol, ethanol, 2-propanol, ether solvent such as diethyl ether, ester solvent such as ethyl acetate, hydrocarbon solvent such as toluene, aprotic solvent such as acetonitrile, and a mixture thereof
• an optically resolved salt may be also, as necessary, treated with acid or base in a conventional manner to give in a free form.
• the adenine compound, or a pharmaceutically acceptable salt thereof of the present invention activates toll-like receptor (TLR), specifically TLR7, and is useful as an immune-response modifier and a therapeutic or preventive agent for diseases such as diseases associated with abnormality of immune response (e.g., autoimmune diseases and allergic diseases), various infectious diseases wherein an immune response is desired to be activated or cancer.
• TLR toll-like receptor
• the adenine compound or a pharmaceutically acceptable salt thereof of the present invention is useful as a therapeutic or preventive agent for diseases including the following (1) to (8).
• the adenine compound or a pharmaceutically acceptable salt thereof of the present invention has a TLR activating effect, more specifically a TLR7 activating effect.
• the adenine compound or a pharmaceutically acceptable salt thereof of the present invention also shows interferon- ⁇ - and interferon-y-inducing activity, and IL-4/IL-5 producing inhibition activity, and acts as an agent with helper T cell type 1 (Th1 cell)/helper T cell type 2 (Th2 cell) selective immunomodulating activity.
• Th1 cell helper T cell type 1
• Th2 cell helper T cell type 2
• it is preferably useful as a therapeutic or preventive agent for allergic diseases caused by Th2 cell such as asthma, COPD, allergic rhinitis, allergic conjunctivitis or atopic dermatitis due to its Th2 cell selective immunosuppressive action.
• the adenine compound or a pharmaceutically acceptable salt thereof of the present invention is useful for treatment of airway obstruction diseases/conditions such as asthma or COPD, or for reducing the risk of these diseases.
• the “preventive agent” is adminstered to a patient, who has not been affected with certain disease or who has no problem in a health condition at the time of administration of the agent, in order to prevent the disease or prevent the symptoms of the disease from worsening.
• the "prevention” (or “preventive ") is expected to be suitable particularly for a person who has previous history of certain disease or be at increased risk for such disease.
• a person at risk for certain disease or deplopment of symptoms has a family history of such disease or can be identified by genetic diagnosis for such diseases.
• an oral preparation may include capsules, powders, tablets, granules, subtle granules, syrups, liquids, suspensions, etc.
• a parenteral preparation may include injections, drips, eye-drops, preparations for intrarectal administration, inhalations, air sprays (e.g., aerosols, dry powders, or liquid/suspensions for sprays, aerosols, or cartridge sprays for inhalators or insufflators, etc.), lotions, gels, ointments, creams, transdermal absorbents, transmucosal absorbents, nasal preprations, eardrops, tapes, transdermal patches, cataplasms, external powders, etc.
• preparations may be prepared according to a conventional technique, and may contain conventional carriers, fillers, binders, lubricants, stabilizers, disintegrants, buffers, solubilizing agents, isotonic agents, surfactants, preservative agents, perfumes, and further optionally contains 2 or more kinds of additives for preparations.
• the adenine compound or a pharmaceutically acceptable salt thereof of the present invention may be incorporated with a pharmaceutically acceptable carrier in a manner known to those skilled in the art to prepare a pharmaceutical composition suitable for each dosage form.
• the adenine compound or a pharmaceutically acceptable salt thereof may be formed into a pharmaceutical composition comprising as an active ingredient 0.05 to 99% by weight, preferably 0.05 to 80% by weight, more preferably 0.1 to 70% by weight, more preferably 0.1 to 50% by weight of the compound.
• liquid preparations such as emulsions and syrups may be prepared by optionally using additives for preparations including water; sugars such as sucrose, sorbit, fructose; ethanol; glycols such as polyethyleneglycol, propyleneglycol, glycerol; oils such as sesame oil, olive oil, soy bean oil; preservative such as p-hydroxybenzoic esters; sweetener such as saccharin; thickener such as carboxymethylcellulose; flavors or colorants such as strawberry flavor, peppermint flavor, etc.
• Solid preparations such as capsules, tablets, powders, granules, etc. may be prepared by optionally compounding the following carriers.
• excipient such as lactose, glucose, sucrose, sorbitol, mannitol (mannite), cellulose derivatives; disintegrant such as starch (e.g., potato starch, cornstarch, amylopectin), sodium alginate; lubricant such as magnesium stearate, calcium stearate, polyethyleneglycol, wax, paraffin, talc; a binder such as polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylcellulose, gelatine; surfactant such as fatty ester; plasticizer such as glycerin, etc.
• excipient such as lactose, glucose, sucrose, sorbitol, mannitol (mannite), cellulose derivatives
• disintegrant such as starch (e.g., potato starch, cornstarch, amylopectin), sodium alginate
• lubricant such as magnesium stearate, calcium stearate, polyethyleneglycol, wax,
• sugar coated tablets it may be coated by concentrated carbohydrate solutions, optionally containing gum arabic, gelatine, talc, titanium dioxide, etc., on tablet cores prepared by using the above fillers.
• tablets may be film-coated by appropriate polymers dissolved in organic solvents which may be easily distilled away.
• Soft gelatine capsules may be prepared by, for example, compounding the present compound with vegetable oil or polyethyleneglycol.
• Hard gelatine capsules may be prepared by using granules of the present compound which may be prepared by optionally compounding any one of the above carriers.
• liquid preparations in the form of injections, drips, eye-drops, eardrops, etc. may be preferably prepared as sterilized isotonic liquid preparations.
• the injections may be prepared by using aqueous media comprising saline solution, glucose solution, or a mixture of saline solution and glucose solution.
• the preparations for intrarectal administration may be prepared by using carriers such as cacao butter, and usually prepared in the form of suppositories.
• the ointments, creams and gels usually contain 0.01 to 10% by weight of the present compound, and to aqueous or oily base may be optionally added preferable thickener and/or gelatinizing agent and/or solvent.
• the base includes water and/or oil such as liquid paraffin, vegetable oil such as peanut oil or castor oil, or solvent such as polyethyleneglycol.
• the thickener and gelatinizing agent include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethyleneglycol, lanolin, bee wax, carboxypolymethylene and cellulose derivative and/or glyceryl monostearate and/or nonionic emulsifier.
• the lotions usually contain 0.01 to 10% by weight of the present compound, and may be formulated by aqueous or oily base and may typically comprise emulsifier, stabilizer, dispersing agent, precipitation inhibitor or thickener.
• the external powders usually contain 0.01 to 10% by weight of the present compound, and may be formed by preferable powder base such as talc, lactose or starch.
• the drips may be formulated by aqueous or nonaqueous base and may contain dispersing agent, solubilizer, precipitation inhibitor or preservative.
• the spray e.g., spray, aerosol, dry powder preparation, etc.
• the aerosol appropriate for inhalation may be either suspension or solution, and typically contains the present compound and any appropriate propellants such as fluorocarbon or hydrogen-containing chlorofluorocarbon or a mixture thereof. Specifically, it contains hydrofluoroalkane, particularly 1,1,1,2-tetrafluoroethane, heptafluoroalkane (HFA) such as 1,1,1,2,3,3,3-heptafluoro-n-propane, or a mixture thereof.
• the aerosol may optionally contain additional preparation excipient well-known to those skilled in the art such as surfactant (e.g., oleic acid or lecithin) and cosolvent (e.g., ethanol), etc. Specifically, it may include inhaler known as "TurbuhalerTM".
• capsule or cartridge of gelatine used in inhaler or ventilator may be formulated containing a powder mixture and preferable powder base such as lactose or starch for inhalation of the compound used in the present invention.
• a powder mixture such as lactose or starch for inhalation of the compound used in the present invention.
• Each capsule or cartridge usually contains 20 ⁇ g to 10 mg of the present compound.
• the compound used in the present invention may be provided without an excipient such as lactose.
• the adenine compound or a pharmaceutically acceptable salt thereof of the present invention may be finely ground into 10 ⁇ m or less to suspend in fatty acid with 8 to 20 carbon atoms or a salt thereof (e.g., oleic acid), bile acid salt, phospholipid, alkyl saccharide, fully-fluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersing agent.
• the adenine compound of the invention can be administered as a preparation for local administration.
• the preferable preparation includes ointment, lotion (solution or suspension), cream, gel, tape, transdermal patch, poultice, spray, aerosol, dry powder preparation, water/suspensions for cartridge sprays for inhaler or ventilator, eye-drops, eardrops, nose drops, transdermal patches, lung absorbents, airway absorbents or external powders, etc.
• the ratio of the active compound used in the present invention is generally 0.001 to 10% by weight, preferably 0.005 to 1% by weight depending on the forms of preparations.
• the ratio used in powders for inhalation or ventilation is in the range of 0.1 to 5% by weight.
• Each quantitative dose or "whiff amount" in the aerosol preferably contains 20 ⁇ g to 2000 ⁇ g, preferably about 20 ⁇ g to 500 ⁇ g of the compound used in the present invention.
• the administration may be once or several times a day, for example 2, 3, 4 or 8 times a day, for example 1, 2 or 3 doses each.
• the pharmacological activity may be measured in any assessments well-known to those skilled in the art, preferably in vitro assessments. Specific measuring method includes the one discribed in Examples in the present specification.
• the present invention also encompasses a combination therapy for treating diseases described in the present specification wherein the compound of the formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of the formula (1) or a pharmaceutically acceptable salt thereof is sequentially or simultaneously administered in combination with one or more of other following medicaments.
• the medicaments for treating inflammatory disease, COPD, asthma and allergic rhinitis include TNF- ⁇ inhibitor such as anti TNF monoclonal antibody (e.g., Remicade, CDP-870 and adalimumab) or TNF receptor immunoglobulin molecule (e.g., enbrel); locally- or systemically-administered nonselective cyclooxygenase: COX-1/COX-2 inhibitor (e.g., piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamate such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylate salt such as aspirin), COX-2 inhibitor (e.g., meloxicam, celecoxib, rofec
• the present invention also encompasses a combination of the present compounds with leukotriene biosynthetic inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activated protein (FLAP) antagonist, for example zileutone; ABT-761; fenleutone; tepoxalin; Abbott-79175; Abbott-85761; N-(5-substituted)-thiophen-2-alkylsulfonamide; 2,6-di-tert-butylphenolhydrazone; methoxytetrahydropyrane such as Zeneca ZD-2138; SB-210661; pyridinyl-substituted-2-cyanonaphthalene compound such as L-739010; 2-cyanoquinoline compound such as L-746530; MK-591, MK-886 and BAY-X-1005, etc.
• leukotriene biosynthetic inhibitor for example zileutone; ABT-761; fenleutone;
• the present invention also encompasses a combination therapy of the present compound with leukotriene (LT) B4, LTC4, LTD4, LTE4 receptor antagonist selected from the following group: phenothiazine compound such as L-651392; amidino compound such as CGS-25019c; benzoxalamine such as ontazolast; benzenecarboximidamide such as BIIL284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, Verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP45715A) and BAY-X-7195, etc.
• phenothiazine compound such as L-651392
• amidino compound such as CGS-25019c
• benzoxalamine such as ontazolast
• benzenecarboximidamide such as BIIL284/260
• compounds such as
• the present invention also encompasses a combination therapy of the present compound with phosphodiesterase (PDE) inhibitor such as methyl xanthanin including theophylline and aminophylline; selective PDE isoenzyme including PDE4 inhibitor, isoform PDE4D inhibitor or PDE5 inhibitor.
• PDE phosphodiesterase
• the present invention also encompasses a combination therapy of the present compound which is orally or parenterally administered with, for example, histamine H1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastin, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine and mizolastine, etc.
• histamine H1 receptor antagonist such as cetirizine, loratadine, desloratadine, fexofenadine, acrivastin, terfenadine, astemizole, azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine and mizolastine, etc.
• the present invention also encompasses a combination therapy of the present compound with histamine type 4 receptor antagonists.
• the present invention also encompasses a combination therapy of the present compound with ⁇ 1/ ⁇ 2 adrenaline receptor agonist and vasoconstrictive sympathetic stimulant such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride, and ethyl norepinephrine hydrochloride.
• ⁇ 1/ ⁇ 2 adrenaline receptor agonist and vasoconstrictive sympathetic stimulant such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydro
• the present invention also encompasses a combination therapy of the present compound with anticholinergic agent including muscarinic receptor (M1, M2 and M3) antagonist such as atropine, biotin, glycopyrrolate, ipratropium bromide; tiotropium bromide; oxytropium bromide; pirenzepine; and telenzepine.
• anticholinergic agent including muscarinic receptor (M1, M2 and M3) antagonist such as atropine, biotin, glycopyrrolate, ipratropium bromide; tiotropium bromide; oxytropium bromide; pirenzepine; and telenzepine.
• the present invention also encompasses a combination therapy of the present compound with ⁇ -adrenaline receptor agonist including ⁇ receptor subtypes 1 to 4 such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolte
• the present invention also encompasses a combination therapy of the present compound with insulin-like growth factor type 1 (IGF-1) mimic.
• IGF-1 insulin-like growth factor type 1
• the present invention also encompasses a combination therapy of the present compound with inhaled glucocorticoid such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate.
• the present invention also encompasses a combination therapy of the present compound with matrix metalloprotease inhibitor, specifically stromelysin, collagenase, gelatinase, aggrecanase, particularly collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11), MMP-9 and MMP-12 inhibitor.
• matrix metalloprotease inhibitor specifically stromelysin, collagenase, gelatinase, aggrecanase, particularly collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10) and stromelysin-3 (MMP-11), MMP-9 and MMP-12 inhibitor.
• the present invention also encompasses a combination therapy of the present compound with chemokine receptor regulators of antagonists of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (CC family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (C-X-C family); C-X3-C family such as CX3CR 1.
• the present invention also encompasses a combination therapy of the present compound with cytokine function regulator including cytokine or medicaments acting on cytokine signaling pathway, for example ⁇ -, ⁇ - and ⁇ -interferon, interleukin (IL) including IL1 to 15, and interleukin antagonist or inhibitor.
• cytokine function regulator including cytokine or medicaments acting on cytokine signaling pathway, for example ⁇ -, ⁇ - and ⁇ -interferon, interleukin (IL) including IL1 to 15, and interleukin antagonist or inhibitor.
• cytokine function regulator including cytokine or medicaments acting on cytokine signaling pathway, for example ⁇ -, ⁇ - and ⁇ -interferon, interleukin (IL) including IL1 to 15, and interleukin antagonist or inhibitor.
• IL interleukin
• the present invention also encompasses a combination therapy of the present compound with antibodies and antagonists regulating Ig functions such as immunoglobulin (Ig), immunoglobulin preparations, anti IgE antibody (omalizumab).
• Ig immunoglobulin
• immunoglobulin preparations immunoglobulin preparations
• anti IgE antibody omalizumab
• the present invention also encompasses a combination therapy of the present compound with systemically- or locally-administered antiinflammatory drugs such as thalidomide and derivatives thereof, retinoid, dithranol and calcipotriol.
• systemically- or locally-administered antiinflammatory drugs such as thalidomide and derivatives thereof, retinoid, dithranol and calcipotriol.
• the present invention also encompasses a combination therapy of the present compound with antibacterial agents such as penicillin derivative, tetracycline, macrolide, ⁇ -lactam, fluoroquinolone, metronidazole and inhaled aminoglycoside; and antiviral agents including acyclovir, famciclovir, balacyclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin; zanamivir, oseltamivir; enzyme inhibitor such as indinavir, nelfinavir, ritonavir and saquinavir; nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine, zidovudine; nonnucleoside reverse transcriptase inhibitor such as nevirapine and efavirenz.
• antibacterial agents such as penicillin derivative, tetracycline,
• the present invention also encompasses a combination therapy of the present compound with medicaments known as therapeutic agents for cancer.
• Preferable agents include the following (i) to (ix).
• Step (i) The compound obtained in Step (i) (40 g) was dissolved in a 19 % solution of sodium butoxide in butanol, and the mixture was heated under reflux for 6 hours.
• the obtained suspension was cooled to room temperature, diluted with water, and extracted with diethyl ether.
• the organic layer was washed with water, dried, and concentrated under reduced pressure.
• the residue was dissolved in a mixture of hexane and diethyl ether for crystallization, and the obtained crystals were collected by filtration to give the title compound. Yield: 19g, 64 %.
• Step (ii) The compound obtained in Step (ii) (30 g) was dissolved in dichloromethane (200 ml), and thereto was added N-bromosuccinimide (27 g) in portions under stirring at room temperature, and then, the mixture was stirred at room temperature overnight. To the mixture was added a 20 % aqueous sodium thiosulfate, and the separated aqueous layer was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated saline solution, and dried. The obtained solution was filtered through silica gel, and concentrated under reduced pressure.
• Step (vi) To the compound obtained in Step (vi) (7.1 g, 19.6 mmol) was added dichloromethane (140 ml), and to the resulting suspension was added thionyl chloride (4.3 ml), and the mixture was stirred at 5° for 2 hours. To the mixture was added toluene (30 ml), and the solvent was evaporated. Toluene (100 ml) was added to the residue, and the solvent was evaporated, and dried under reduced pressure to give the sub-title compound as pale yellow solid (7.2 g, 19.6 mmol). Yield: 99 %.
• Example 8 1-[4-(6-Amino-2-butoxy-8-oxo-7,8-dihydropurin-9-yl-methyl)benzyl]piperidine-4-carboxylic acid amide (135 mg, 60 %)
• Example 12 6-Amino-2-(2-methoxyethoxy)-9-[4-(4-phenylpiperazin-1-ylmethyl)benzyl]-7,9-dihydropurin-8-one (86 mg, 45 %)
• Example 13 6-Amino-2-(2-methoxyethoxy)-9-[4-(4-phenoxypiperidin-1-ylmethyl)benzyl]-7,9-dihydropurin-8-one (170 mg, 45 %)
• Example 14 6-Amino-9-(4-dimethylaminomethylbenzyl)-2-(2-methoxy-ethoxy)-7,9-dihydropurin-8-one (130 mg, 63 %)
• Example 15 6-Amino-9- ⁇ 4-[(diisopropylamino)methyl]benzyl ⁇ -2-(2-methoxyethoxy)-7,9-dihydropurin-8-one (51 mg, 29 %)
• Example 16 6-Amino-2-(2-methoxyethoxy)-9-(4- ⁇ [(2-methoxyethyl)methylamino]methyl ⁇ benzyl)-7,9-dihydropurin-8-one (62 mg, 25 %)
• Example 18 6-Amino-9-(4-cyclohexylaminomethylbenzyl)-2-(2-methoxyethoxy)-7,9-dihydropurin-8-one (41 mg, 19 %)
• Example 19 6-Amino-2-(2-methoxyethoxy)-9- ⁇ 4-[(methylphenylamino)-methyl]benzyl ⁇ -7,9-dihydropurin-8-one (185 mg, 100 %)
• Example 20 6-Amino-9- ⁇ 4-[(benzylmethylamino)methyl]benzyl ⁇ -2-(2-methoxyethoxy)-7,9-dihydropurin-8-one (210 mg, 85 %)
• Example 22 6-Amino-2-cyclopropylmethoxy-9-(4-morpholin-4-ylmethylbenzyl)-7,9-dihydropurin-8-one) (58 mg, 42 %)
• Example 25 6-Amino-9-(4- ⁇ [(2-methoxyethyl)methylamino]methyl ⁇ -benzyl)-2-(4, 4, 4-trifluorobutoxy)-7,9-dihydropurin-8-one (64 mg, 57 %)
• Example 26 6-Amino-9-[4-(4-methoxypiperidin-1-ylmethyl)benzyl]-2-(2,2,2-trifluoroethoxy)-7,9-dihydropurin-8-one (140 mg, 77 %)
• Example 27 6-Amino-9-[4-(4-oxopiperidin-1-ylmethyl)benzyl]-2-(2,2,2-trifluoroethoxy)-7,9-dihydropurin-8-one (45 mg, 35 %)
• Example 41 6-Amino-2-butoxy-9-[6-(4-methyl-[1, 4]diazepan-1-yl)-pyridin-3-ylmethyl]-7,9-dihydropurin-8-one (125 mg, 64 %)
• Example 42 6-Amino-2-(2-methoxyethoxy)-9-[6-(4-methylpiperazin-1-yl)pyridin-3-ylmethyl]-7,9-dihydropurin-8-one (115 mg, 46 %)
• Example 48 6-Amino-2-butylamino-9-(6-piperazin-1-ylpyridin-3-ylmethyl)-7,9-dihydropurin-8-one (79 mg, 35 %)
• Example 50 6-Amino-2-butylamino-9- ⁇ 6-[(3-dimethylaminopropyl)-methylamino]pyridin-3-ylmethyl ⁇ -7,9-dihydropurin-8-one (32 mg, 15 %)
• Example 54 6-Amino-2-butylamino-9-[6-(2-dimethylaminoethoxy)-pyridin-3-ylmethyl]-7,9-dihydropurin-8-one (27 mg, 13 %)
• Example 55 6-Amino-2-butylamino-9-[6-(4-dimethylaminobutoxy)-pyridin-3-ylmethyl]-7,9-dihydropurin-8-one (24 mg, 15 %)
• Example 58 6-Amino-2-butylamino-9-[5-chloro-6-(2-dimethylamino-ethoxy)pyridin-3-ylmethyl]-7,9-dihydropurin-8-one
• Example 56 Using 2-butylamino-9-(5,6-dichloropyridin-3-ylmethyl)-8-oxoadenine obtained in Example 56, the title compound was obtained in a similar manner to Example 52 (104 mg, 54 %).
• Example 60 The compound of Example 60 (240 mg, 0.5 mmol) and 20 % Pd(OH) 2 /C (50 mg) were added to methanol (10 mL), and the mixture was stirred under hydrogen atmosphere for 5 hours. The catalyst was removed, and water was added thereto, and the precipitated solid was collected by filtration to give the title compound (170 mg, 76 %).
• This solid and lithium aluminum hydride (74 mg, 2 mmol) were added to THF (10 mL), and the mixture was stirred under ice-cooling for 2 hours. The insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added thionyl chloride (0.3 mL) and dichloromethane (5 mL), and the mixture was stirred at 40°C for 2 hours. The solvent was removed by evaporation, and to the residue were added morpholine (0.2 mL), diisorpopylethylamine (0.5 mL) and DMF (5mL), and the mixture was heated at 80°C with stirring for 2 hours.
• Example 65 6-Amino-9-(4-diisopropylaminomethylbenzyl)-2-ethoxy-7,9-dihydropurin-8-one, white solid (Yield: 0.098 g, Yield: 61 %)
• Example 66 6-Amino-2-ethoxy-9-(4-piperidin-1-ylmethylbenzyl)-7,9-dihydropurin-8-one), White solid, Yield: 0.14 g (90 %).
• Example 68 6-Amino-2-ethoxy-9-(4-morpholin-4-ylmethylbenzyl)-7,9-dihydropurin-8-one), White solid, Yield: 0.11 g (68 %).
• Example 69 6-Amino-2-ethoxy-9-(4-thiomorpholin-4-ylmethylbenzyl)-7,9-dihydropurin-8-one, White solid, Yield: 0.13 g (80 %).
• Example 70 6-Amino-2-ethoxy-9-[4-(4-methylpiperazin-1-ylmethyl)-benzyl]-7,9-dihydropurin-8-one, White solid, Yield: 0.094 g (58 %).
• Step (ii) The compound obtained in Step (ii) (1.34 g, 3.35 mmol) was dissolved in THF (100 ml), and thereto was added a 28 % aqueous ammonia (33 ml), and the mixture was stirred at room temperature for 5 days. After concentration, water was added to the residue, and the precipitated solid was collected by filtration, and dried to give the sub-title compound (1.17 g, 3.06 mmol) as a white solid. Yield: 92 %.
• Step (iii) The compound obtained in Step (iii) (1.17 g, 3.06 mmol) was dissolved in DMF (10 ml), and thereto were added acetic anhydride (0.58 ml, 6.12 mmol) and triethylamine (0.85 ml, 6.12 mmol), and the mixture was stirred at room temperature for 16 hours. After concentration, water was added to the residue, and the precipitated solid was collected by filtration and dried to give the sub-title compound (1.30 g, 3.06 mmol) as a white solid. Yield: 100 %.
• Step (v) The compound obtained in Step (v) (0.84 g, 2.38 mmol) was dissolved in chloroform (20 ml), and the mixture was cooled to 0°C. To the mixture was added sodium acetate (0.98 g, 11.9 mmol), and thereto was slowly added dropwise a solution of bromine (0.76 g, 4.76 mmol) in chloroform (5 ml). The mixture was warmed to room temperature, and stirred for 3 hours. The mixture was cooled to 0°, and thereto were added a saturated sodium hydrogen carbonate solution, a saturated aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform three times.
• Step (vi) The compound obtained in Step (vi) (0.77 g, 1.78 mmol) was suspended in methanol (30 ml), and thereto was added 2M aqueous sodium hydroxide solution (15 ml), and the mixture was stirred under reflux for 1.5 hour. The mixture was cooled to 0°C, and the mixture was neutralized with 1 M hydrochloric acid. The mixture was extracted with chloroform three times to give the sub-title compound (0.61 g, 1.78 mmol) as a pale brown solid. Yield: 100 %.
• Step (i) To a solution of the compound obtained in Step (i) (2.90 g, 10 mmol) in NMP (20 mL, 0.5M) were added iPr 2 EtN (3.88 g, 3.0 eq) and 4-pyridylmethylamine (5.0 mL, 25 %v/v.), and the mixture was stirred at 180°C for 20 hours under stirring in an autoclave. After confirming the disappearance of the starting compound by LCMS, the mixture was cooled to room temperature, and water (500 mL) and 5 % MeOH-CHCl 3 (1.0 L x 2) were added thereto and separated. The organic layers were combined and washed with a saturated saline solution (500 mL).
• Step (iii) To a suspension of the compound obtained in Step (iii) (352 mg, 0.8 mmol) in methanol (200 mL, ca. 5.0 x 10 -3 M) was added potassium methoxide (1.12 g, 20 eq.), and the mixture was heated with stirring in an autoclave at 120° for 12 hours. After confirming the disappearance of the starting compound by LCMS, the mixture was cooled to room temperature, and water (300 mL) and a 25 % EtOH-chloroform (500 mL x 2) were added thereto. The mixture was separated and the solvent was removed by evaporateion.
• Step (iv) To a suspension of the compound obtained in Step (iv) (200 mg, 0.512 mmol) in CHCl 3 (51 mL, 0.01M) was added SOCl 2 (1.8 mL, 50 eq.), and the mixture was stirred at room temperature for 3 hours. After confirming the disappearance of the starting compound, the solvent was removed by evaporation to give the sub-title compound (205 mg) as white crystals. Yield: 100 %.
• Step (v) The compound obtained in Step (v) (74 mg, 0.19 mmol) was dissolved in DMF (1 ml), and thereto was added dimethylamine (2.0M THF solution, 3 ml), and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated by an evaporator, and the thereto was added at 0°C 1 % aqueous ammonia (6 ml). The precipitated solid was collected by filtration and purified by silica gel column to give the title compound (20 mg) as a white solid. Yield: 27 %.
• Example 77 6-Amino-2-(2-methoxyethoxy)-9-[4-(4-pyridin-4-yl-piperazin-1-ylmethyl)benzyl]-7,9-dihydropurin-8-one (165 mg, 82 %)
• Example 78 6-Amino-9-(4- ⁇ [bis-(2-methoxyethyl)amino]methyl ⁇ benzyl)-2-(2-methoxyethoxy)-7,9-dihydropurin-8-one (108 mg, 56 %)
• Example 80 6-Amino-2-butoxy-9-(4- ⁇ [(2, 3-dihydroxypropyl)methyl-amino]methyl ⁇ benzyl)-7,9-dihydropurin-8-one (136 mg, 57 %)
• Example 81 6-Amino-2-butoxy-9-(4- ⁇ [(2-dimethylaminoethyl)methyl-amino]methyl ⁇ benzyl)-7,9-dihydropurin-8 - one (92 mg, 47 %)
• HEK 293 cells to which human TLR7 or rat TLR7 plasmid and reporter plasmid (NF-kB-SEAP) were stably introduced, were suspended in DMEM medium (10 % FBS, 1 % NEAA, 10 ug/mL blastocidin S HC1, 100 ug/mL Zeocin), and seeded into a 96-well plate in an amount of 90 ⁇ l/well (hTLR7/seap-293: 20, 000 cells/well, rTLR7/seap-293: 25, 000 cells/well).
• DMEM medium 10 % FBS, 1 % NEAA, 10 ug/mL blastocidin S HC1, 100 ug/mL Zeocin
• test compound (DMSO stock solution (2 ⁇ l) was diluted into 100-fold with the medium (200 ⁇ l)) was added into the cells seeded in the 96-well plate in an amount of 10 ⁇ l/well (final concentration: 1nM to 10 ⁇ M, common ratio: 3). The side of the plate was lightly patted for stirring the content of the plate, and the plate was incubated for 20 hours in a CO 2 incubator. To the cells that were stimulated with a test compound was added a substrate for reporter assay (substrate for SEAP, pNPP) in an amount of 50 ⁇ l/well.
• substrate for reporter assay substrate for SEAP, pNPP
• Example 1 Compound EC 50 (nM) Example 1 7.2 Example 2 0.9 Example 3 1.8 Example 4 2.5 Example 5 2.7 Example 13 18.7 Example 23 14.8 Example 29 7.6 Example 37 1.1 Example 56 1.3 Example 58 3.7 Example 68 5.5
• Example 76 In a similar manner to Example 76, the compounds as listed in Table 3 may be prepared.
• the compounds as listed in Table 4 may be prepared by a method disclosed in the present description.
• Step (i) The compound obtained in Step (i) (1.50 g, 4.37 mmol) was dissolved in DMF (50 ml), and thereto were added 1, 3-dibromopropane (4.4 ml, 43.7mmol) and potassium carbonate (0.60 g, 4.37mmol), and the mixture was stirred at 70°C for 6 hours. The solvent was removed by evaporation, and water was added thereto. The mixture was extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the sub-title compound (0.48 g) as a white solid.
• Step (ii) The compound obtained in Step (ii) (0.15 g, 0.32 mmol) was dissolved in THF (3 ml), and thereto was added a solution of 30 % methylamine/methanol solution (3 ml), and the mixture was stirred at room temperature for 9 hours. The solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to give the sub-title compound (0.13 g) as a white solid.
• the title compound can be prepared by reacting the compound obtained in Step (iii) with benzyl bromide in acetonitrile in the presence of potassium carbonate.
• the compounds as listed in the following Table 5 can be prepared in a similar manner to the method disclosed in the above Steps (i) to (iv) and Example 52.
• the title compound can be prepared by reacting the compound obtained in Step (i) with benzyl bromide in DMF in the presence of potassium carbonate.
• the compounds 88-2 and 88-3 as listed in the following Table 6 can be obtained in a similar manner to the above Step (i), (ii).
• the title compound may be prepared by reacting the compound obtained in Example 90 with thionyl chloride in dichloromethane.
• the title compound can be prepared by reacting the compound of Example 91 with morpholine. In a similar manner to Example 1, the compounds of Examples 93 to 103 were obtained.
• Example 102 6-Amino-9-[4-(4-cyclopentylpiperazin-1-ylmethyl)benzyl]-2-(2-methoxyethoxy)-7,9-dihydropurin-8-one
• Example 104 6-Amino-2-butoxy-9- ⁇ 6-[(2-dimethylaminoethyl)methylamino]pyridin-3-ylmethyl ⁇ -7,9-dihydropurin-8-one
• Example 106 6-Amino-9-[5-chloro-6-(4-methyl-[1,4)diazepan-1-yl)-pyridin-3-ylmethyl]-2-(2-methoxyethoxy)-7,9-dihydropurin-8-one
• Example 110 6-Amino-9-[6-(3-dimethylamino-2,2-dirnethylpropoxy)-pyridin-3-ylmethyl]-2-(2-methoxyethoxy)-7,9-dihydropurin-8-one)
• Example 120 6-Amino-9-[5-chloro-6-(3-dimethylamino-2,2-dimethylpropoxy)pyridin-3-ylmethyl]-2-(2-methoxyethoxy)-7,9-dihydropurin-8-one
• Example 122 6-Amino-9- ⁇ 5-chloro-6-[3-(4-methylpiperazin-1-yl)-propoxy]pyridin-3-ylmethyl ⁇ -2-(2-methoxyethoxy)-7,9-dihydropurin-8-one
• 6-Bromopyridin-3-yl)methanol (2.58 g, 13.7 mmol) was dissolved in THF (25 mL) and cooled to 0°C. The solution was added sequentially with diisopropylmethylamine (2.36 mL, 13.7 mmol) and methanesulfonyl chloride (1.06 mL, 13.7 mmol), stirred at 0°C for 1 hour. The mixture was concentrated by evaporator, and thereto added water and extracted with chloroform, and then dried over magnesium sulphate and concentrated to give the sub-title compound as pale orange oil (3.64 g, 13.7 mmol, quantitative).
• Step (iii) 9-[6-(2-[1,3]Dioxan-2-ylethyl)pyridin-3-ylmethyl]-8-methoxy-2-(2-methoxyethoxy)-9H-purin-6-ylamine
• Step (ii) The compound obtained in Step (ii) (0.56 g, 1.37 mmol) was dissolved in THF (12 ml), and thereto added tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol) and (1, 3-dioxane-2-yl ethyl) zinc bromide (0.5 M in THF, 19.2 ml, 9.6 mmol). The mixture was stirred at room temperature for 15 hours. 1M hydrochloric acid was added to neutralize, and the solvent was removed by an evaporator. To the residue was added with a saturated saline solution, extracted with chloroform, dried over magnesium sulphate and concentrated under vacuum.
• Example 85 In a similar manner to Example 85, the following compounds were tested.
• the human TLR7 binding activity (EC50) of each compound is shown in Table 6.
• a test compound was administered to B6C3F1 mice (Charles River Japan, Inc.) via tail vein at the dose of 1 mg/kg intravenously. After 3 hours, total blood was collected into a sample tube containing heparin. Plasma was prepared from total blood after centrifugation (3, 000 rpm, 10 min, at room temperature) and stored at -20°C.
• Murine fibroblasts (L929/ 2-5AS-Luc), which constitutively expressed luciferase gene in which the promoter region for 2'-5'-oligoadenylate synthase was cloned, was seeded into 96-well plate at 4 ⁇ 10 4 cells/well, and cultured for overnight with diluted plasma or mouse IFN-a. After Luclite (Perkin Elmer) was added to the plate, the luciferase activity was measured with TopCount (Perkin Elmer).
• IFN- ⁇ production inducing activity Compound Dose Mouse IFN- ⁇ (IU/mL)
• Example 54 1mg/kg 53.6 ⁇ 6.5 a )
• Example 42 1mg/kg 30.0 ⁇ 7.3
• Example 10 1mg/kg 7.3 ⁇ 1.6
• OV-HM ovarian carcinoma-bearing B6C3F1 mouse was prepared by intradermally inoculating 1 ⁇ 10 6 viable OV-HM cells in back skin. Tumor was surgically removed ten days after the tumor incubation under isoflurane anesthesia. On Day 11, Day 14, Day 17, Day 20, Day 24, Day 28, and Day 32, a test compound was administered via tail vein at the dose of 1 mg/kg. On Day 35, mouse was euthanized, and lung was collected from the mouse. Metastasized tumor nodules in lung was counted, and the frequency of the metastasized mice was calculated in each group. The results are shown in Table 8. The compounds tested significantly inhibited the metastasis into lung, showing antitumor activity.
• Table 8 Antitumor activity Compound Dose Frequency of metastasis Number of tumor Example 63 1mg/kg 0/6 0.0** vehicle 10mL/kg 5/5 >64.5 ** p ⁇ 0.01 vs vehicle group (Wilcoxon)
• Example 135 6-Amino-2-(2-methoxyethoxy)-9-[6-(1-propylpiperidin-4-yloxy)pyridin-3-ylmethyl]-7,9-dihydropurin-8-one

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